TSHR is a member of the leucine-rich repeat-containing G protein-coupled receptors. Both TSHR and its ligand TSH have evolved to acquire specificity, minimize cross-reaction to other glycoprotein hormone receptors (GPHR), modulate cognate interaction and thereby thyrotropic activity. TSHR sequences available from two life-orders teleost and mammals were analyzed. Teleost TSHR with low affinity are expressed in many non-thyroidal tissues and show a tendency to gene duplication. In some teleosts TSHR has limited specificity, and in others extremely high constitutive activity suggesting the possibility of ligand-independent receptor function. Although mammalian TSHR, in contrast to other GPHR, maintains relatively high constitutive activity, the thyrotropic activity of TSH appears to decline in hominoids including humans, probably as part of metabolic adaptation to the changing environment. Critical TSHR residues that determine hormone specificity have been identified in the (Leucine-rich repeats (LRRs), and others within the cysteine-rich C- flanking region that determines hormonal activation as well as receptor silencing. Transmembrane (TM) helices, particularly the TM 5 & 6, are likely involved in receptor homodimerization and a unique motif in TM7 appears essential to receptor silencing and internalization. Surprisingly, ternary structures in the intracellular domain as opposed to specific sequence motifs are critical for intra-cellular TSHR trafficking. It is evident that progress in understanding structure-function relationships of TSHR and its ligand can be further stimulated by inclusion of evolutionary analysis of their primary, secondary and tertiary structure. Such integrated approach should also contribute to the rational design of highly efficacious therapeutics with either agonistic or antagonistic properties.